Diols from acyloins

The Corey-Winter reaction provides a useful method for the preparation of olefins that are not accessible by other routes. For instance it may be used for the synthesis of sterically crowded targets, since the initial attack of phosphorus at the sulfur takes place quite distantly from sterically demanding groups that might be present in the substrate molecule. Moreover the required vicinal diols are easily accessible, e.g. by the carbon-carbon bond forming acyloin ester condensation followed by a reductive step. By such a route the twistene 10 has been synthesized ... 

Acyloin condensation of diester 30a with sodium in liquid ammonia, followed by direct hydrogenation in the presence of Adam s catalyst, furnished the diol 32 in 49% yield. Diol 32 was transformed into the cyclic thiocarbonyl derivative (80% yield) which after heating with trimethylphosphite [14] afforded twistene 33 in 50% yield. Hydrogenation of 33 gave a compound identical in all respects with twistane 1. From the diester (-)-30a (+)-twistene was obtained, m.p. 35.5-36.5 °C, +... 

The generation of the (2S,3R) diol 4 from 1 is the consequence of a multlenzymic process involving two distinct chemical operations (2) (i) Addition of a unit equivalent to acetaldehyde onto thesiface of the carbonyl carbon atom of the unsaturated aldehyde to form a (3R) -hydroxyketone, in an acyloin of type condensation, and (ii) reduction of the latter intermediate on the face of the carbonyl group to give rise to the diol actually isolated (Eq. 2). 

The hydroxynitrile lyase (HNL) class of enzymes, also referred to as oxynitrilases, consists of enzymes that catalyze the formation of chiral cyanohydrins by the stereospecific addition of hydrogen cyanide (HCN) to aldehydes and ketones (Scheme 19.36).275 279 These chiral cyanohydrins are versatile synthons, which can be further modified to prepare chiral a-hydroxy acids, a-hydroxy aldehydes and ketones, acyloins, vicinal diols, ethanolamines, and a- and P-amino acids, to name a few.280 Both (R)- and (.S )-selective HNLs have been isolated, usually from plant sources, where their natural substrates play a role in defense mechanisms of the plant through the release of HCN. In addition to there being HNLs with different stereo-preferences, two different classifications have been defined, based on whether the HNL contains a flavin adenine dinucleotide (FAD) co-factor. 

With the exception of the diol 9, that was obtained from the corresponding aldehyde in up to 35% yield, most of the chiral diols mentioned above were isolated in yields of only 20-25%. The formation of the acyloin-type condensation products is in competition with the much more efficient reduction of the carbonyl carbon and saturation of the double bond of the unsaturated aldehydes that were used as substrates. We became interested in the mode of reduction of particular aldehydes such as 54-56 (Scheme 8) in a study of the total synthesis of natural a-tocopherol (vitamin E) (23). We expected to obtain chiral alcohols that would be useful for conversion into natural isoprenoids from the reduction of the a-double bond of the above aldehydes. Indeed, 54-56 afforded up to 75% yield of the saturated carbinols 57-59 by treatment with yeast. Whereas the ee of 57 and 58 was ca 85%-90%, that of 59 is 99%, as shown by NMR experiments on the (-)-MTPA derivative (24). The synthetic significance of carbinol 59 was based on the structural unit present in natural isoprenoids (see brackets in structural formulas). This protected synthon can be unmasked by ozonolysis, as indicated by the high yield conversion of 59 into (S)-(-) -3-methyl-y-butyrolactone 60 (Scheme 9). Product 59 is a bifunctional chiral intermediate which does not need protective manipulation in that... 

From a synthetic point of view, bond forming steps are the most important reactions of radical ions [202]. Several principle possibilities have been described in Section 8.1 and are summarized in Scheme 52. Many carbo- and heterocyclic ring systems can be constructed by (inter- and intramolecular) radical addition to alkenes, alkynes, or arenes. Coupling of carbonyl radical anions leads to pinacols either intra-or inter-molecular which can be further modified to give 1,2-diols, acyloins or alkenes. Radical combination reactions with alkyl radicals afford the opportunity to synthesize macrocyclic rings. These radical ion-radical pairs can be generated most efficiently by inter- or intramolecular photoinduced electron transfer. 

Corey and Wat17 found that the method of forming cycloolefins from allylic dihalides and nickel carbonyl provides an unusually efficient route for the formation of large rings. Because it leads to cyclic 1,5-dienes, it makes available a variety of cyclic structures not obtainable in a practical way via the acyloin synthesis. Diacetylenic diols (10) were converted by selective reduction into the corresponding cis.cis- and owu,/ra -ethylenic diols followed by reaction with PBr3 to form the diallylic dibromides (12), which were then cyclized with nickel carbonyl. 

The final twistane synthesis we will consider originates from the one-bond disconnection indicated by Path D in Unnatural Products-1. Just as with Path A, the synthesis uses a Diels-Alder reaction to establish the bicyclo[2.2.2]octane substructure of key intermediate 9. The cycloaddition of cyclohexadiene 43 and methyl propiolate afforded a mixture of regioiso-meric cycloadducts 44 and 45. Catalytic hydrogenation of the mixture occured from the sterically most accessible face of the olefin to afford meso-compound 46 and its diastereomer 9. Diester 9 was subjected to an acyloin condensation, and catalytic hydrogenation of the resulting a-hydroxyketone gave diol 47. A Corey-Winter reaction was used to convert 47 to 49 via thionocarbonate 48. Catalytic hydrogenation completed the synthesis. 

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